Intended for healthcare professionals

Clinical Review

Huntington’s disease

BMJ 2010; 340 doi: https://doi.org/10.1136/bmj.c3109 (Published 30 June 2010) Cite this as: BMJ 2010;340:c3109
  1. Marianne J U Novak, clinical research fellow12,
  2. Sarah J Tabrizi, professor of clinical neurology, honorary consultant neurologist and neurogeneticist 13
  1. 1National Hospital for Neurology and Neurosurgery, London WC1N 3BG
  2. 2Wellcome Trust Centre for Neuroimaging, UCL Institute of Neurology, London WC1N 3BG
  3. 3Department of Neurodegenerative Disease, UCL Institute of Neurology
  1. Correspondence to: S Tabrizi sarah.tabrizi{at}prion.ucl.ac.uk
  • Accepted 8 April 2010

Summary points

  • Huntington’s disease causes motor, cognitive, and psychiatric impairment

  • Predictive and diagnostic genetic testing are available through specialist centres

  • Genetic testing for the disease has many implications for patients and families

  • The disease currently has no cure, but many therapeutic options exist to improve symptoms

  • Optimal care usually requires input from a multidisciplinary team

Huntington’s disease is a devastating inherited neurodegenerative disease characterised by progressive motor, cognitive, and psychiatric symptoms. Patients may present with any of these symptoms, and familiarity with the phenotype is therefore important. Chorea and loss of balance are early symptoms that patients notice, although families often notice cognitive or personality changes before this.

Sources and selection criteria

This review is based on our experience of leading (SJT) and working in (MJUN) the multidisciplinary Huntington’s disease clinic at the National Hospital for Neurology and Neurosurgery, supported by an up to date literature review performed using PubMed and a review of the Cochrane database.

The disease occurs in all racial groups but is most common in people of northern European origin. Its prevalence in the Western hemisphere is 7-10/100 000.w1 The mean age of onset of symptoms is 40 years, but juvenile onset (<20 years) and older onset (>70 years) forms are well recognised. The Huntington’s Disease Association (HDA) has records of 6161 adults with symptomatic Huntington’s disease and 541 children with juvenile Huntington’s disease (in England and Wales) at the time of writing. This is a conservative estimate of prevalence because it includes only those people in contact with the HDA, and it suggests that the true prevalence of the disease is higher than previously thought.1

Although relatively uncommon, Huntington’s disease can be devastating for patients and their families. People who are at risk of developing the disease because of a family history face difficult decisions about genetic testing. We review the features of Huntington’s disease, recent advances in management, and advances in the practice and ethics of genetic testing that may be relevant to a wide spectrum of health professionals.

What are the clinical features of Huntington’s disease?

The disease was originally named Huntington’s chorea after George Huntington, who wrote the first detailed description in 1872. More recently, however, the name has changed to Huntington’s disease to reflect the fact that chorea is not the only important manifestation of the disease. There are many non-motor symptoms that may be more disabling and distressing than the motor symptoms.2 3 4 One study assessed the effect of cognitive and motor symptoms on the ability of 67 people with early Huntington’s disease to carry out activities of daily living, and found that cognitive impairment was associated with reduced functional ability independent of motor impairment.2

Imaging and postmortem studies have shown that the disease is characterised by cerebral atrophy.5 6 Atrophic changes are initially seen most prominently in the striatum (part of the basal ganglia) and later become more widespread, as shown in fig 1.

Figure1

Fig 1 Statistical parametric map showing grey matter volume loss in patient groups compared with controls. Pre-A and pre-B are premanifest Huntington’s disease gene carriers with estimated time to clinical disease onset greater than and less than 10.8 years, respectively. (This was estimated using CAG repeat length and age in a formula that has been well validated and used extensively in research into Huntington’s diseasew10). Stage 1 and stage 2 are patients with early manifest disease who have no functional impairment and mild functional impairment, respectively. The figure shows progressive grey matter volume loss in the caudate and putamen (striatum) initially, followed by the cerebral cortex. Results are adjusted for age, sex, study site, and total intracranial volume and are corrected for multiple comparisons using family-wise error at P<0.05. Reproduced from Tabrizi et al,7 with permission from the Elsevier Publishing Group

Huntington’s disease progresses over 15-20 years. Characteristic symptoms reflect a triad of motor, cognitive, and psychiatric manifestations of the disease (box 1). The onset of disease is currently defined as the point at which characteristic motor signs develop8; this is when a patient moves from being a “premanifest gene carrier” to having “manifest” disease. This distinction is somewhat arbitrary because most patients develop cognitive or psychiatric symptoms (or both) during the prodromal (“premanifest”) period, often many years before any motor signs are seen.7 9 w2

Box 1 Common symptoms of Huntington’s disease

Motor symptoms
  • Chorea, dystonia, loss of postural reflexes, bradykinesia, rigidity

Cognitive symptoms
  • Disorganisation as a result of difficulties with planning, initiating, and organising thoughts, activities, and communication; perseveration; impulsivity; perceptual distortions; lack of insight; distractibility; difficulty in learning new information

Psychiatric
  • Depression, obsessive-compulsive disorders, anxiety, irritability, apathy, hypersexuality (uncommon), psychosis (uncommon)

Metabolic
  • Weight loss, sleep disturbance

Others
  • Dysphasia (combination of motor and language difficulties), dysphagia (combination of motor problems, impulsivity, and distractibility)

Motor symptoms

The motor symptoms of Huntington’s disease can be divided into two categories: added involuntary movements such as chorea and impaired voluntary movements, which cause limb incoordination and impaired hand function. These symptoms are worsened by loss of postural reflexes. The pattern of symptoms tends to change over time, with chorea declining and dystonia, rigidity, and bradykinesia becoming more marked.

Cognitive symptoms

Cognitive impairment includes slowing of thought processing and deterioration of executive functions (high level cognitive processes that control other aspects of cognitive function). Typically, patients report difficulty with multitasking, concentration, and short term memory. Thinking style becomes more concrete and less efficient, and the planning, initiation, and organisation of time, thoughts, and activities become harder. People with Huntington’s disease are often impulsive and develop psychomotor perseveration. Visuospatial perception can also deteriorate.4 9

Psychiatric symptoms

Depression is one of the most common psychiatric symptoms and occurs as part of the disease, rather than merely as a response to diagnosis. A recent survey of 2835 patients with the disease found that 40% had symptoms of depression, and 50% reported having sought treatment for depression in the past.10 Other reported psychiatric symptoms include obsessive-compulsive symptoms and psychosis.w3-w5

It is important to recognise psychiatric symptoms in Huntington’s disease so that symptomatic treatment can be offered. This may be difficult later in the disease because diagnoses may be obscured by other features of the disease; depression, for example, may be difficult to detect in a patient who has altered facial expressions and tone of voice. Conversely, metabolic symptoms such as weight loss and sleep disturbance may be wrongly attributed to depression.

Suicide risk

Patients with Huntington’s disease are more likely than members of the general population to commit suicide according to a meta-analysis of studies that reported mortality associated with mental disorders (standardised mortality ratio of 290).w6 A survey of 4171 carriers of the Huntington’s gene with premanifest and manifest disease found that 17.5% had suicidal thoughts at or around the time of assessment and 10% of those surveyed had made at least one suicide attempt in the past.11 Suicidal ideation was highest in gene carriers who were nearing the threshold of being diagnosed with manifest disease (those with soft motor signs of Huntington’s disease), and in those who were beginning to lose their functional ability and independence (those with stage 2 disease). Risk factors for suicide in Huntington’s disease include depression and impulsivity.4 Some people with the disease also have suicidal thoughts in the absence of depressionw7: for some, thoughts of suicide seem to be a rational response to their imminent loss of independence.

Metabolic symptoms

Huntington’s disease causes metabolic symptoms, which include catabolic weight loss, endocrine dysfunction, and sleep disturbance.12

Advanced disease

By the time patients have endstage disease they are profoundly disabled. Communication may be severely limited and muteness is common, which can result in agitation and frustration. Huntington’s disease does not cause global dementia, however, and the ability to recognise and interact with people is often preserved. Huntington’s disease is a catabolic condition, and this, combined with marked dysphagia, means that it can be difficult to provide sufficient nutrition to maintain a patient’s weight.

How is Huntington’s disease inherited?

What is the genetic basis of the disease?

Huntington’s disease is a single gene disease with autosomal dominant inheritance. The genetic abnormality is an expanded CAG trinucleotide repeat within the Huntingtin (HTT) gene on chromosome 4, and it can be identified through genetic testing.13 The HTT gene encodes the protein huntingtin, which is essential for normal neural development, although its functions are incompletely understood.14 w8 w9 In Huntington’s disease, the expanded HTT gene encodes a mutant form of huntingtin protein. The mutant protein causes or contributes to the development of Huntington’s disease through many pathogenic mechanisms.15

Offspring of an affected parent have a 50% chance of inheriting the genetic abnormality, and males and females are affected equally. Huntington’s disease does not skip generations.

What is the meaning of CAG repeat length in Huntington’s disease?

A “normal” HTT gene has fewer than 36 repeats. The gene is abnormal, or expanded, if it has 36 or more repeats, and CAG repeats of 40 or more will always cause Huntington’s disease. Genes with CAG repeat lengths between 36 and 39 show reduced penetrance, which means that some people with these lengths will develop Huntington’s disease and some will not; those who do develop disease are likely to develop later onset disease.w10 An intermediate repeat length between 29 and 35 does not cause the disease but may expand into the pathogenic range in future generations.

The instability of intermediate alleles is one cause of sporadic Huntington’s disease, in which the disease develops in someone with no apparent family history. Apparent sporadic Huntington’s disease occurs in 6-8% of new cases of Huntington’s disease,w11 w12 and it can also be caused by unexpected or unknown paternity, or a parent dying before they develop symptoms of the disease. Instability of the CAG repeats can also cause “genetic anticipation,” in which the CAG repeat length increases and causes onset of the disease at a younger age in affected offspring than in the parent. Genetic anticipation is more common when the expanded allele is inherited from a father than from a mother. About 90% of people with juvenile disease (with CAG repeats typically >60) inherit the mutation from their father.w13 w14

CAG repeat length is related to age of onset of disease at a population level: the longer the CAG repeat length, the earlier the onset of symptoms tends to be. However, repeat length only accounts for 50-70% of this variance, and disease onset in an individual cannot be predicted reliably through genetic testing.w15 The CAG repeat length is related less strongly to the rate of disease progression.w16 w17

How is genetic testing undertaken?

Genetic testing for Huntington’s disease is performed by measuring the CAG repeat length in the HTT gene. We will use the term “positive” test result to refer to CAG lengths in the pathogenic fully penetrant CAG repeat range of more than 39 repeats. Testing falls into two categories.

Diagnostic testing is carried out to confirm (or refute) the diagnosis in a patient with symptoms suggestive of Huntington’s disease. It is a test for manifest disease and is most commonly undertaken by neurologists. A positive diagnosis has numerous implications for family members (especially children and siblings) and for the patient, and it is important to offer as much information as possible about the disease and the meaning of a positive diagnosis before testing. Our experience has been that family members’ reactions and coping strategies are linked to how they find out that they are at risk themselves.

Predictive testing is carried out in a person who has no symptoms of the disease, but who is at risk because of their family history. It determines whether that person carries the expanded HTT gene and will develop Huntington’s disease in the future. A positive predictive test result indicates that they will certainly develop Huntington’s disease at some point in the future (unless they die of another cause in the meantime), but it does not tell them when this will happen or what the presenting symptoms will be. Reasons commonly cited for having predictive testing include wishing to relieve uncertainty, to inform decisions about reproduction, and to plan for the future.16 17 Predictive testing is not performed in children. This is because informed consent requires an adult understanding of the consequences of a predictive test result. Consent for predictive testing by a parent would remove from a child their right to autonomy in choosing whether or not to be given this information.

Predictive testing for Huntington’s disease is performed in specialist genetic centres and follows internationally agreed guidelines.18 19 20 These include an initial session of pre-test counselling, followed by a period of reflection, and then a second session of counselling. Post-test counselling must also be available. Matters such as insurance and mortgages are discussed (see below).

Several studies have reviewed the uptake of predictive testing among people at risk; on average, 5-20% of those at risk in the United Kingdom take up the option.21 w18-w20

What ethical considerations surround genetic testing?

Confidentiality and consent

According to internationally agreed guidelines,18 19 20 strict confidentiality is observed before, during, and after predictive testing. No one other than the adult being tested is told about the process without their express permission. This includes partners and family members. Some people with positive predictive Huntington’s disease test results choose not to inform their general practitioner so that the information remains confidential. Written informed consent must be obtained from the patient before either predictive testing or diagnostic testing. If the patient lacks capacity to make the decision themselves for diagnostic testing, consent can be given by an authorised representative.

Having children

Deciding whether or not to have children is often difficult for people with or at risk of having an expanded HTT gene. A minority choose to have either prenatal testing or preimplantation genetic diagnosis, which ensures that their child has a less than 1% chance of carrying the mutant gene. Although couples in which one partner is at risk of or has Huntington’s disease are not usually eligible to adopt, some adoption agencies will consider it, and fostering may also be possible.

Prenatal testing

Prenatal testing is usually carried out via chorionic villus sampling between 11 and 13 weeks of pregnancy. Pre-test counselling is important: potential parents need to be sure that they will terminate the pregnancy if their fetus is found to have an expanded HTT gene, otherwise their child will grow up in the shadow of a predictive test for which they did not consent. This would violate the autonomy of the child. A termination cannot, of course, be forced on a couple who change their mind after receiving a positive test result. These considerations, together with the potential risk of miscarriage after chorionic villus sampling or amniocentesis, mean that prenatal testing cannot be undertaken lightly. In practice, a couple who disclose a family history of Huntington’s disease for the first time in pregnancy only rarely proceed to prenatal testing.

Preimplantation genetic diagnosis

This technique is available through specialist units. In preimplantation genetic diagnosis, embryos are created using normal in vitro fertilisation procedures and then tested for the expanded HTT gene. Unaffected embryos are implanted. Overall, about one in five cycles results in a live birth, but success rates vary. The Human Fertilisation and Embryology Association website contains more details (www.hfea.gov.uk/).

Exclusion (non-disclosing) prenatal testing and preimplantation genetic diagnosis

Exclusion (non-disclosing) prenatal testing or preimplantation genetic diagnosis can be carried out for couples in which one partner is at risk but does not wish to have a predictive test. With this test the potential parents do not find out their own Huntington’s disease gene status. The test requires blood samples from several family members, and linkage techniques are used rather than testing for the CAG expansion (see fig 2 for more details). A “high risk” result means that the fetus is at 50% risk of developing Huntington’s disease—the same risk as the at risk parent. A couple undergoing this test may choose to terminate a pregnancy at 50% risk. Clearly this test requires detailed discussion with the couple beforehand. In practice, very few of these tests are performed, but it is a helpful option for some couples.

Figure2

Fig 2 Use of linkage analysis for prenatal testing. Adapted, with permission, from material of the Guy’s and St Thomas’ NHS Foundation Trust reproductive medicine clinic and assisted conception unit

What are the implications of a positive gene test for the individual?

Emotional implications

A patient who receives a diagnosis of manifest Huntington’s disease learns that he or she has a slowly progressive incurable disease. A person who receives a positive predictive test experiences the extra burden of being uncertain when the disease will begin to take effect. Most people who have genetic testing for Huntington’s disease will have watched a parent develop the disease, will be familiar with the change in personality and cognition that it causes, and will know what effect their illness will have on those around them.

Since direct genetic testing for Huntington’s disease became available in 1993, a steadily increasing cohort of premanifest gene carriers has been created. Many of this group may not wish to engage with health or social services until they develop manifest disease, whereas others value emotional and practical support to help them deal with the implications of a predictive test result.

In 1996, one study followed up 135 Canadians who had entered a predictive testing programme.w21 Adverse events, including psychological distress, substance misuse, and relationship breakdowns, were recorded in seven of the 37 who received a positive result compared with eight of the 58 who received a negative result. (The remaining subjects received equivocal results or chose not to proceed with testing.) One subject in each group reported suicidal ideation.

A positive predictive test can come as a relief, however, because some people find a positive test result easier to cope with than the uncertainty of being at risk. As discussed above, only a minority of people at risk choose to have predictive testing; these people are a self selecting group, and the aim of genetic counselling is to ensure that they are equipped to deal with their predictive test result. Diagnostic testing can also be helpful in removing uncertainty—for example, a diagnosis of Huntington’s disease could alleviate the distress caused by an unexplained change in personality.

Practical implications: insurance and employment

In 2001, the Association of British Insurers (ABI; the trade association for the UK insurance industry; www.abi.org.uk/) and the UK government agreed a moratorium on access to any predictive genetic test results by insurance companies who are ABI members. In general, insurers will weight applicants who have a family history of Huntington’s disease but cannot require them to take a predictive genetic test. People at risk of Huntington’s disease can apply for up to £500 000 of life insurance, £300 000 of critical illness insurance, and income protection that pays benefits of up to £30 000 a year without disclosing the results of any predictive genetic test. Huntington’s disease is, however, the one disease that is exempt from a total ban on disclosure; applicants must disclose Huntington’s disease predictive test results if they apply for life insurance over £500 000. A negative predictive test result will bring insurance premiums back in line with those of people without a family history of Huntington’s disease. This insurance moratorium is due to be reviewed in 2011.

A positive predictive test does not need to be declared when applying for travel insurance in the UK, but manifest disease does. Specialist companies with experience of insuring people with pre-existing medical conditions are helpful, and the HDA can provide details of appropriate contacts.

Under the 1995 Disability Discrimination Act in the UK, it is illegal for employers to discriminate against someone who is disabled by dismissing them or by treating them negatively because of their disability. We strongly recommend that patients with Huntington’s disease who feel that their ability to work is deteriorating inform their employers about their diagnosis to ensure that their job is legally protected. Once diagnosis is revealed, regular assessment should take place according to occupational risk. The legal situation for people at risk of Huntington’s disease because of their family history is less clear cut, and there is currently no law in the UK to prevent discrimination against those with a genetic diagnosis (in employment, or elsewhere). A working group of the Human Genetics Commission in the UK is currently examining this area and is due to report in 2011. In the United States, the 2008 Genetic Information Nondiscrimination Act prohibits discrimination on the basis of genetic information in employment and health insurance provision.

In the UK, asymptomatic gene carriers are not obliged to disclose a positive predictive test result to their employer unless a health questionnaire has a specific question on this. In reality, however, some employers may place restrictions, based on family history, on the work of people who are at risk or are asymptomatic gene carriers. The police, for example, have separate rules for each authority but may ask employees at risk to have regular neurological reviews. The UK armed forces are a special case: until recently, applicants to the armed forces who were at risk of Huntington’s disease because of their family history were accepted only if they had received a negative predictive test result. This policy is now being reconsidered, with alternatives such as a shorter term of service being offered. As with patients with manifest Huntington’s disease, we recommend regular review of premanifest gene carriers as appropriate for their occupational level of risk.

Research on genetic discrimination in Huntington’s disease is limited, but a recent survey of 233 tested and untested people at risk of Huntington’s disease in Canada found that 6.4% reported genetic discrimination related to employment.w22 Anecdotal evidence also suggests that some premanifest gene carriers have been discriminated against in the UK.

What are the implications of a positive Huntington’s disease gene test for the family?

A positive predictive or diagnostic Huntington’s disease test has a huge effect on the partner and family of the person tested. Someone close to the person tested faces the prospect of becoming a carer, often when relatively young, and probably for many years. A new diagnosis of Huntington’s disease has implications for siblings and children who suddenly become at risk of acquiring the disease.

Rarely, an at risk person’s positive test result will in effect tell another family member their own gene status. For example, if the grandchild of someone with Huntington’s disease, who will have a 25% risk of carrying the Huntington’s disease gene, has a positive test, their at risk parent must be a gene carrier. If the intermediate family member does not wish to know their gene status, every effort should be made to find a solution that is acceptable for all parties. This situation is rare, but guidelines state that if no agreement is reached after all attempts for an acceptable compromise, the wishes of the person at 25% risk should be followed and testing performed.

The dynamics of families affected by Huntington’s disease are often complicated, particularly between those who do and those who do not carry the expanded gene. It may create supportive and close knit families, but it can also be extremely divisive. The result is often a high level of resilience and care within the family, mixed with anger, resentment, and guilt. Anger and resentment can have many outlets: towards a parent who has passed on their expanded gene; towards unaffected family members, particularly siblings; or towards older generations who have not been open about the presence of Huntington’s disease in the family. Guilt also has many manifestations, such as that felt by a parent who has passed on their expanded gene to a child, or who has become symptomatic and now sees himself or herself as a burden to the family, or survivor guilt in people who have had a negative predictive test. Receiving a negative test result when other family members have tested positive can be an isolating experience too.

Most affected families will contain more than one person with the disease, with several more at risk of developing the disease in the future, creating a scenario where one person first endures the burden of being a carer and being bereaved by the disease, and later being a patient who needs care.

How is Huntington’s disease managed?

The aim of treatment is to manage symptoms and improve quality of life. No current treatments can slow disease progression, although promising disease modifying treatments are being tested preclinically in animal models of Huntington’s disease.15 22 There are many effective options for symptomatic management, however, both drug based and non-drug based.23 24 Tables 1 and 2 summarise those drugs commonly used for symptom management. Their choice is based mainly on clinical experience because the evidence base for drugs in Huntington’s disease is small.25 26 27 28 Tetrabenazine has the best evidence of efficacy in Huntington’s disease and has been shown to reduce chorea in a randomised controlled clinical trial.w23 Box 2 contains details of where to access further information about drug treatments in Huntington’s disease.

Table 1 Symptomatic management of movement disorder in Huntington’s disease

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Table 2 Symptomatic management of psychiatric symptoms in Huntington’s disease

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Box 2 Sources of information about symptoms of Huntington’s disease

  • The HDA website: contains easily accessible information about Huntington’s disease (www.hda.org.uk/)

  • The definitive book about Huntington’s disease: Huntington’s disease, 3rd ed. Bates GP, Harper PS, Jones L, eds. Oxford Monographs on Medical Genetics 45. Oxford University Press, 2002

  • Further information about psychiatric symptoms: Paulsen JS, Ready RE, Hamilton JM, Mega MS, Cummings JL. Neuropsychiatric aspects of Huntington’s disease. J Neurol Neurosurg Psychiatry 2001;71:310-4

  • Further information about psychiatric symptoms in premanifest disease: Julien CL, Thompson JC, Wild S, Yardumian P, Snowden JS, Turner G, et al. Psychiatric disorders in preclinical Huntington’s disease. J Neurol Neurosurg Psychiatry 2007;78:939-43

  • Further information about non-neurological features: Van der Burg JM, Bjorkqvist M, Brundin P. Beyond the brain: widespread pathology in Huntington’s disease. Lancet Neurol 2009;8:765-74

Many non-drug measures are effective in the management of Huntington’s disease, and these are often more helpful than drugs (table 3).3 29 Once again, the evidence for these treatments is limited, but their use is based on extensive clinical experience. Their provision usually requires a multidisciplinary approach.3 29

Table 3 Non-drug based management of Huntington’s disease

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We recommend that patients are referred to a specialist multidisciplinary Huntington’s disease clinic where possible, so that they can access care from healthcare professionals experienced in the management of the disease. Support from professionals in the community remains vital, and optimal care is typically provided by a multidisciplinary team that includes some or all of the following: general practitioners, neurologists, geneticists, psychiatrists, physiotherapists, occupational therapists, speech and language therapists, dieticians, community mental health teams, and social workers. HDA advisers are available throughout England and Wales to support patients and their families, and to provide educational input for healthcare professionals caring for people with the disease (www.hda.org). The Scottish Huntington’s Association and the Huntington’s Disease Association of Northern Ireland provide similar support.

Managing the movement disorder

The first step is to decide whether symptoms need treating. Patients are often not bothered by early chorea, for example, and may not even be aware of it. As chorea develops, however, it can interfere with voluntary activities like writing or eating, and it often causes falls, making intervention necessary. Chorea can be distressing in itself, and patients often find themselves accused of drunkenness by people unaware of their diagnosis.

Non-drug interventions should be considered first. Chorea often varies with posture or positioning, and devices such as padded chairs or wrist and ankle weights to reduce the amplitude of chorea may be helpful. Shoes with non-slip soles and grab rails around the home can improve safety, and assessment of the home by an occupational therapist is often extremely useful. Physiotherapy can also help optimise mobility, and can be especially beneficial early in the disease to preserve mobility and independence for as long as possible. Like most involuntary movements, chorea is worsened by stress, anxiety, and depression, so treating these and providing a calm predictable environment are beneficial.

If these measures are not sufficient to control symptoms, drugs can be tried. These are unlikely to prevent chorea completely, but they can dampen down symptoms considerably, and tetrabenazine is generally the first choice. It can exacerbate or trigger psychiatric symptoms, so it should be avoided in patients with a history of depression or other psychiatric disorders, and in these patients, or in those in whom symptoms are not controlled with tetrabenazine, the atypical neuroleptics are helpful. Of these, olanzapine is our first choice because it is an effective anti-chorea drug that also promotes weight gain, suppresses irritability, and improves sleep—all of which are useful side effects in Huntington’s disease.

Movement suppressing drugs used in the earlier stages may however exacerbate the impaired movements that develop later on. They will often need to be reduced and eventually stopped, so regular reassessment is vital.

Managing cognitive and psychiatric manifestations

Recognising and acknowledging that these symptoms are probably caused by Huntington’s disease is important so that strategies can be developed to deal with them. It is important to ask depressed patients about suicidal thoughts, and to take a proactive approach to the treatment of psychiatric symptoms. Treatment of depression in Huntington’s disease is with standard antidepressants. Although there is not an established evidence base for the treatment of depression in Huntington’s disease, our experience is that antidepressants are often very effective. Psychological treatments, such as cognitive behavioural therapy, can also be helpful in selected patients. This can also be a useful way for people with premanifest disease to learn cognitive strategies that will stand them in good stead once they develop cognitive and psychiatric symptoms. We know of no controlled trials of this treatment in Huntington’s disease, although one case study reported benefit for a patient with premanifest disease.w24 Support from local community mental health teams is often invaluable.

No drug treatments are available for cognitive symptoms, but coping strategies can often be adopted to overcome problems or compensate for them. Difficulty with multitasking is an example of a common early symptom; concentrating in a busy office can be difficult and tension may develop in relationships with colleagues. This, in turn, will increase stress and exacerbate the underlying problem with concentration. Once these problems have been identified, appropriate compensatory strategies can be devised, such as moving into a quiet office and reducing workload. Employers have a statutory duty to optimise the working environment for people with a disability where possible, although this needs to be approached sensitively.

Apathy is also a challenging symptom to manage and can be difficult to differentiate from depression; it may be worth considering a trial of antidepressants if this is the case. It is important to gently impose structure on the day, because patients often find that having an appointment to aim for, such as coffee with a friend, helps them to initiate activities and organise their behaviour. It can be difficult for people with Huntington’s disease to initiate activities, but once started they are often able to participate fully with encouragement and support from carers.

End of life care

Planning for end of life care raises several ethical problems that often relate to how far medical interventions should be taken in patients who no longer have the capacity to make their wishes known. We find that advanced decisions to refuse treatment (previously known as advanced directives) can be extremely helpful. They give patients the security of knowing that their wishes will be carried out, even if they are no longer able to make decisions or communicate, and they relieve relatives of the responsibility of making choices. Advanced decisions to refuse treatment and end of life care should be raised as early as possible so that they can be discussed by the patient and their loved ones. The Independent Mental Capacity Advocate service (www.dh.gov.uk/en/SocialCare/Deliveringadultsocialcare/MentalCapacity/IMCA/index.htm) provided via the Department of Health can be helpful if a patient does not have capacity and his or her next of kin is unable or unwilling to make decisions on the patient’s behalf.

As Huntington’s disease progresses, it often becomes increasingly difficult to provide care at home, and a nursing home may be the best option. Insertion of a gastrostomy tube may be appropriate in patients who are unable to maintain adequate nutrition and body weight. Box 3 contains sources of information for palliative management in Huntington’s disease.

Box 3 Sources of information about the management of Huntington’s disease

  • As well as containing general information about Huntington’s disease, the HDA website contains information about disease management, including extensive advice on non-medical management (www.hda.org.uk/). Guidelines for allied health professionals caring for patients with Huntington’s disease (for example, physiotherapy, speech and language therapy, dietary advice) are accessible via the site

  • An excellent review of management: Phillips W, Shannon KM, Barker RA. The current clinical management of Huntington’s disease. Mov Disord 2008;23:1491-504

  • Cochrane review of medical treatment: Mestre T, Ferreira J, Coelho MM, Rosa M, Sampaio C. Therapeutic interventions for symptomatic treatment in Huntington’s disease. Cochrane Database Syst Rev 2009;3:CD006456

  • A comprehensive review of an ideal care pathway for Huntington’s disease: shown in figure 2 in the article Huntington’s disease: GP guide to clinical management. El-Nimr G, Barrett K. Prescriber 19 May 2006

  • A good source of information about palliative care in Huntington’s disease (some comments are specific to the US, but the general principles are universal): Moskowitz CB, Marder K. Palliative care for people with late-stage Huntington’s disease. Neurol Clin 2001;19:849-65

Conclusions

Managing the many facets of Huntington’s disease can be challenging and is best served within multidisciplinary settings. We continue to learn about how to improve our services from our patients and their families. The current major push to find disease modifying treatments, coupled with the existence of a specific and sensitive diagnostic genetic test, means that in the future treatments might be initiated in the premanifest phase, with the hope of delaying or halting the disease process itself.

Current research

  • There is currently a major push to find disease modifying drugs and new treatments for the symptoms of Huntington’s disease, and many new developments have been made in recent years

  • In February 2010, the results of the MermaiHD study were announced as a press release: pridopidine, a dopamine stabiliser (also known as Huntexil, previously known as ACR16) was shown to improve voluntary motor symptoms in a phase III trial of 437 patients with Huntington’s disease. Publication in a peer reviewed form is awaited

  • Previous clinical trials have evaluated creatine and coenzyme Q10 among other compounds, but have not demonstrated efficacy. Many patients continue to buy them over the counter and comparison trials of the two substances, funded by the National Institutes for Health, are ongoing

  • A phrase III trial of latrepirdine (Dimebon), is currently taking place in multiple sites, including several in the UK

  • Exciting progress has been made recently in identifying several other pathways that are potential targets for future therapeutic intervention and clinic trials. This is too large a subject to cover in detail, but see Imarisio et al for a comprehensive review.15 Potential therapeutic approaches include:

    • Enhancing clearance of mutant huntingtin by cellular clearance mechanisms: several compounds being tested in mouse models of Huntington’s disease aim to promote clearance of the mutant protein, huntingtin, which is generated by the expanded HTT gene

    • Histone deacetylase inhibitors: these target the transcriptional dysregulation that occurs early in the pathogenesis of Huntington’s disease

    • Inhibitors of proteolytic cleavage of full length mutant huntingtin: these would prevent production of the potentially toxic N-terminal fragment

    • Gene silencing: to switch off expression of the mutant gene itself

  • To achieve optimal effect, future disease modifying treatments will probably consist of a combination of treatments targeting key pathogenic pathways, similar to the treatment of HIV or cancer

  • Much progress has been made in developing and evaluating sensitive biomarkers that will help to measure the effects of disease modifying treatments in future clinical trials, particularly in the premanifest and early stages of the disease. Track-HD7 and Predict-HD9 are major international collaborative studies that have increased our understanding of the course of Huntington’s disease and which biomarkers are the best for monitoring this

Additional educational resources for patients, families, and healthcare professionals

These websites are accessible and excellent sources of information for both patients and families and healthcare professionals:

A patient’s perspective

I am not as whole as I was. My thought processes have slowed down and it takes enormous self discipline to do ordinary things like getting dressed—it’s exhausting. I recognised these changes in myself years before anyone else did, and it is important that other people (including healthcare professionals) just accept this—the changes don’t have to be measurable. They can’t reassure me that all is well but they can support me. By accepting that changes are happening, they give me permission to adapt my life at an early stage. I have changed my high powered job to an “ordinary” job, for example, which has taken pressure off me and allowed me to put energy into other things. The end stage of Huntington’s disease will happen no matter what, but I will live most of my life before this point and I want to make the most of it.

Sue Walters, Hertfordshire

Notes

Cite this as: BMJ 2010;340:c3109

Footnotes

  • Thanks to Sue Walters, Elisabeth Rosser, David Craufurd, Edward Wild, Alison Lashwood, Ruth Sands, Rachael Scahill, Sheila Simpson, Cath Stanley, and Rachel Taylor for valuable discussions and input. Many thanks to Ray Young for the figures.

  • Contributors: Both authors were responsible for the conception and design of this paper. MJUN initially drafted the paper and SJT reviewed and amended it. SJT is guarantor.

  • Competing interests: All authors have completed the Unified Competing Interest form and declare that: (1) SJT holds grants from the Medical Research Council (G0700877), Wellcome Trust (075696/Z/04/Z), and Cure Huntington’s Disease Initiative; (2) They have no relationships with companies that might have an interest in the submitted work; (3) They have no spouses, partners, or children with financial relationships that may be relevant to the submitted work; and (4) They have no non-financial interests that may be relevant to the submitted work.

  • Provenance and peer review: Not commissioned; externally peer reviewed.

  • Patient consent obtained.

References

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